Compositions and methods for targeting cerebral circulation and treatment of headache

ABSTRACT

Methods and compositions for targeting cerebral circulation and treatment of headache include formulations comprising a pharmacologically active substance in a transdermal formulation, which is topically applied to an area of skin superficial to a carotid artery, a temporal artery, a vertebral artery, or to a tender spot associated with a headache. Particularly preferred formulations include a xanthine derivative (e.g., theophylline, caffeine, aminophylline), and may further comprise ketoprofen. Contemplated methods further include methods of advertising use of contemplated compositions.

[0001] This application is a continuation-in-part of, and claims thebenefit to the PCT application with the serial number PCT/US01/26459,filed Aug. 23, 2001.

FIELD OF THE INVENTION

[0002] The field of the invention is compositions and methods fortargeting cerebral circulation, and particularly relates to treatment ofheadache.

BACKGROUND OF THE INVENTION

[0003] Less severe to moderate headaches (e.g., tension headaches) areexperienced by about seventy five percent of Americans, while more thanforty percent of Americans experience six or more less severe tomoderate headaches per year. Approximately twenty percent of peoplesuffer at least one severe headache per year, and in North America alone28 million people have been diagnosed with recurring migraines. Severeheadaches often limit a person significantly in their ability to engagein life, and it is estimated that approximately 157 million working daysper year are lost due to headaches.

[0004] It is generally believed that vascular headaches and particularlymigraine are at least in part caused by swelling of blood vessels in thescalp, in the meninges (i.e., pia mater, dura mater, and arachnoidmembrane), and/or in the brain itself. Both scalp and meninges areinnervated by pain fibers, onto which the swollen vessels are thought topress. The swelling of the blood vessels can be triggered by a varietyof factors, including intrinsic factors (e.g., stress), and/or extrinsicfactors. For example, caffeine acts as a vasoconstrictive agent in thebrain, and consequently many people experience headaches upon caffeinewithdrawal.

[0005] There are various pharmacological treatments known in the art toreduce headaches. For example, many people use Aspirin™ (Acetylicsalicylic acid) or Tylenol™ (Acetaminophen) to reduce their headache.Although such over-the-counter drugs are often relatively effective toat least reduce some of the pain, they tend to incur, and especially inhigher dosages and/or prolonged administration, significant side effects(e.g., ulcers, increase in coagulation time, etc.).

[0006] In alternative treatments, pharmacologically active agents aresystemically administered to target receptors that are functionallyinvolved in vasoconstriction of blood vessels in the cerebralcirculation, thereby relieving the pressure perceived as a headache.Examples for such pharmacologically active agents include triptans(e.g., Sumatriptan and Rizatriptan), and various ergots that target the5HT receptors, which stimulate cerebral vasoconstriction [Hargreaves inCephalalgia (2000) 20 Suppl 1:2-9].

[0007] In a still further example, caffeine and other methylxanthines(although vasodilating in the periphery) stimulate vasoconstriction inthe cerebral circulation. Such methylxanthines are probably effective bystimulation of the release of endogenous epinephrine and norepinephrine,both of which are potent cerebral vasoconstrictors [Muller-Schweinitzerand Fanchamps in Adv. Neurol.(1982) 33:343-356]. Caffeine is a componentof several over-the-counter migraine and headache medications. However,in known formulations caffeine needs to be orally ingested insubstantial quantities to reduce a headache, which often producesundesirable side effects (e.g., excessive central nervous stimulation).

[0008] Although there are various methods and compositions known in theart to reduce headache and/or migraine, all or almost all of them sufferfrom one or more disadvantage. Therefore, there is still a need toprovide improved methods and compositions for treatment of headacheand/or migraine.

SUMMARY OF THE INVENTION

[0009] Methods and compositions are provided which are employed totarget cerebral circulation and to treat headache. More particularly,contemplated methods and compositions include formulations comprising apharmacologically active substance in a transdermal formulation, whichis topically applied to an area of skin superficial to a carotid artery,a temporal artery, a vertebral artery, or to a tender spot associatedwith a headache.

[0010] In one aspect of the inventive subject matter, contemplatedtransdermal formulations comprise a skin penetration enhancer (e.g., anazone derivative, a synthetic terpene, oleic acid,N-methyl-2-pyrrolidone, an epsilon-aminocaproic acid ester, a lecithinorganogel, a pluronic-lecithin-organogel, or an aromaticS,S-dimethyliminosulfurane). Particularly preferred pharmacologicallyactive substances include xanthine derivatives (e.g., caffeine,theophylline, or aminophylline) in a concentration of at least 1% to70%. Contemplated formulations may further include ketoprofen(2-(meta-benzoylphenyl)propionic acid) as a muscular-active substance ina concentration of about 0.5% (wt) to 50% (wt).

[0011] In another aspect of the inventive subject matter, a method oftreating a person having a headache includes a step in which a tenderspot associated with the headache on a body surface (particularly neck,face, and scalp) of the person is identified. In a further step,contemplated compositions are topically applied to the tender spot in anamount effective to reduce the headache.

[0012] In a further aspect of the inventive subject matter, a method ofmarketing a product includes one step in which contemplated compositionsare included in the product. In a further step, a person is instructedto identify a tender spot associated with a headache on a body surface,and in a still further step, the person is instructed to topically applythe product to the tender spot in an amount effective to reduce theheadache.

[0013] In yet another aspect, a method of marketing a product includesone step in which contemplated compositions (including skin penetrationenhancer and pharmacological active substance) are included in theproduct, and in which a person is instructed to identify an area of skinsuperficial to a carotid artery, a temporal artery, or a vertebralartery. In a further step, the person is instructed to topically applythe product to the area in an amount effective to direct thepharmacological active substance to a cerebral circulation.

[0014] Various objects, features, aspects and advantages of the presentinvention will become more apparent from the following detaileddescription of preferred embodiments of the invention, along with theaccompanying drawing. dr

BRIEF DESCRIPTION OF THE DRAWING

[0015]FIG. 1 is a schematic view of head and neck of a person depictingexemplary areas of application of contemplated compositions andformulations.

DETAILED DESCRIPTION

[0016] Contemplated Compounds, Compositions, and Formulations

[0017] It is generally contemplated, that cerebral circulation can betargeted with various compositions comprising a pharmacologically activesubstance in a transdermal formulation, and that contemplated compounds(i.e., pharmacologically active substances), compositions, andformulations can advantageously be employed for treatment of variousdiseases or symptoms, particularly headache.

[0018] In a preferred aspect of the inventive subject matter,contemplated compositions include a pharmacologically active substancethat preferably has a vaso-active effect. The term “vaso-active effect”as used herein includes vaso-constrictive (effecting at least 5% luminalconstriction, more typically at least 10% luminal constriction) andvaso-dilatory effects (effecting at least 5% luminal dilation, moretypically at least 10% luminal dilation). Consequently, particularlypreferred pharmacologically active substances include xanthinederivatives according to structure 1, and especially include caffeine,theophylline, and dimeric forms such as aminophylline (ethylene diaminecomplex with theophylline).

[0019] wherein R₁-R₃ are independently hydrogen, methyl, branched orunbranched lower alkyl, all of which may or may not further comprisefunctional groups (e.g., nucleophilic, electrophilic, polar, non-polar,etc.), and which may include one or more conjugated or nonconjugatedτ-bonds. Furthermore, one or more nitrogen atoms may be replaced withanother heteroatom (e.g., O, S, Se, etc.), or be replaced with a carbonatom. Similarly, the carbonyl oxygen may be replaced with atoms otherthan oxygen, or substituted with a functional group (e.g., carboxylicacid, hydroxyl, nitrile, ethynyl, amino, imino, etc.).

[0020] In alternative aspects, suitable pharmacologically activecompounds also include various vaso-active substances other thanxanthine derivatives, and particularly include vitamin B6, digitalis,diuretics, or angiotensin-converting enzyme inhibitors. Whereappropriate, it is also contemplated that nitrate-generating compounds(e.g., nitroglycerin, isosorbide-5-mononitrate, etc.) may be included inalternative compositions and formulations. In still further alternativeaspects, vasodilators may be included to improve cerebral blood flow.

[0021] Where it is especially desirable that contemplated compositionsinclude a muscular-active compound, it is contemplated that all knownmuscle relaxants are contemplated suitable for use herein. The term“muscular-active compound” as used herein refers to all compounds thatmodulate the tonus of a muscle. Particularly contemplatedmuscular-active compounds reduce the tonus of smooth muscles and/orvoluntarily controlled muscles. For example, appropriate musclerelaxants include carisoprodol, cyclobenzaprine, chlorzoxazone,metaxolone, or methocarbamol. However, an especially preferredmuscular-active compounds is ketoprofen (infra).

[0022] In yet further alternative aspects, it is contemplated thatsuitable compounds include all compounds that have a desiredpharmacological activity in the cerebral circulation and/or the brain.For example, alternative drugs include drugs that interact with thehypothalamus, the hypophysis, receptors in the brain, or particularcells (e.g., neuronal cells, glial cells, astrocytes, etc.), which mayor may not be diseased. Consequently, suitable compounds include feverreductants, anti-inflammatory drugs, anti-depressants, anti-coagulants,stimulants, cytokines, and so forth.

[0023] With respect to the amount of contemplated compounds, it shouldbe appreciated that a particular amount of a particularpharmacologically active compound will typically depend on the desiredstrength of the formulation, the type of pharmacologically activecompound, and the particular application of the formulation.Consequently, contemplated compounds may be in the range of less than0.1% w/w to 90% w/w, and even more. More typically, contemplatedcompounds may be in the range of about 1% w/w to 20% w/w.

[0024] It is generally preferred that where the pharmacologically activesubstance is a xanthine derivative according to Structure 1, appropriateamounts will typically be within a range of 1% w/w to about 70% w/w,more preferably within the range of at least 2% w/w to about 50% w/w,and most preferably in the range of at least 4% w/w to about 15% w/w.Muscular-active compounds (e.g., Ketoprofen) are contemplated to beincluded in suitable formulations in a range of about at least 0.5% w/wto about 50% w/w, preferably at least 2% w/w to about 25% w/w, and morepreferably between about at least 4% w/w to about 15% w/w.

[0025] In another preferred aspect of the inventive subject matter,contemplated compositions include a transdermal formulation (i.e.,contemplated compounds are formulated in a transdermal formulation). Theterm “transdermal formulation” as used herein refers to any formulationthat facilitates passage of a pharmacologically active substance acrossthe epidermal layer into at least the papillary, and more preferably thereticular layer of the human dermis. There are numerous transdermalformulations known in the art, and all of the known transdermalformulations are considered suitable for use in conjunction with theteachings presented herein.

[0026] It is generally contemplated that suitable transdermalformulations include ionic compounds (e.g., ascorbate, calciumthioglycolate, cetyl trimethyl ammonium bromide, ionic surfactants,5-methoxysalicylate, etc.), dimethyl sulfoxide and related compounds(e.g., cyclic sulfoxides, decylmethyl sulfoxide, etc.), azone andrelated compounds (e.g., 1-dodecyl azacycloheptan-2-one,N-Dodecyl-2-pyrrolidone, azacycloalkane derivatives,1-geranylazacycloheptan-2-one, etc.). Further contemplated skinpenetration enhancer include solvents (e.g., alkanols, esp. ethanol,dimethyl formamide, polyoxyethylene sorbitan monoesters, propyleneglycol, etc.), or fatty alcohols, fatty acids, and related structures(e.g., aliphatic and lauryl alcohols, dodecyl N,N-dimethylamino acetate,ethyl acetate, alkanoic acids and oleic acids, isopropyl myristate,etc.). Still further contemplated formulations include enzymes (e.g.,papain), amines and amides (e.g., N,N-Diethyl-m-toluamide), complexingagents (e.g., Brij, Pluronic, etc), and N-methyl pyrrolidone and relatedcompounds (e.g., 1,3-Dimethyl-2-imidazolikinone or 2-Pyrrolidone).

[0027] Particularly suitable skin penetration enhancers include azonederivatives, natural and synthetic terpenoid compounds and theiralcohols, oleic acid, N-methyl-2-pyrrolidone, epsilon-aminocaproic acidesters, lecithin organogels, pluronic-lecithin-organogels, aromaticS,S-dimethyliminosulfurane, Padimate O, oil-water emulsions withsub-micron droplets, capsaicin, and various esters of organic acids.

[0028] Contemplated compositions and formulations can be prepared usingvarious protocols, and a particular composition will typically determine(at least in part) a particular protocol. There are numerous methods andprotocols known in the art, and exemplary protocols and transdermalformulations are described in “Topical Drug Bioavailability,Bioequivalence, and Penetration” by Vinod P. Shah, Howard I. Maibach(Editor), Plenum Pub Corp; ISBN: 0306443678, or in “PercutaneousPenetration Enhancers” by Eric W. Smith (Editor), Howard I. Maibach(Editor), CRC Press; ISBN: 0849326052, or in “Pharmaceutical SkinPenetration Enhancement” by Kenneth A. Walters, Jonathan Hadgraft(Editor), Marcel Dekker; ISBN: 0824790170, or in “Drug PermeationEnhancement: Theory and Applications” by D. S. Hseih, Ed. (Dekker, NewYork, 1994), all of which are incorporated by reference herein.

[0029] Consequently, contemplated compositions and formulations aretypically preparations for topical application, and particularly includepreparations in form of a cream, gel, lotion, ointment, salve, or apaste. Alternatively, contemplated compositions and formulations mayalso include preparations in liquid form (e.g., a syrup, tincture,spray, drops, etc.), all of which may or may not be applied with apatch.

[0030] Especially preferred compositions include a xanthine derivativein a concentration of about 4% (wt) to 70% (wt) and ketoprofen in aconcentration of about 0.5% (wt) to 50% (wt). With respect to thexanthine derivative, the same considerations as described above apply.Furthermore, such particularly preferred compositions may be formulatedin a lecithin-containing formulation or a pluronic-lecithin-organogelformulation (supra). It should be especially recognized, thatcompositions including a xanthine derivative or an NSAID have generallybeen described in the art. However, the inventors observed thatformulations including an NSAID other than Ketoprofen generally fail toprovide relief in treatment of a headache, when topically applied to aperson (either to a tender spot, or to an area superficial to a carotidartery, a temporal artery and/or a vertebral artery). It is therefore asurprising result that Ketoprofen is the only NSAID effective intreatment of a headache when used in protocols according to theinventive subject matter (see also examples). While not wishing to bebound by a particular hypothesis or theory, the inventors contemplatethat the effect of Ketoprofen may be at least in part mediated by amuscle-relaxant effect rather than via a suppressive effect ininflammation.

[0031] It should further be appreciated that contemplated compounds(i.e., pharmacologically active substances) expressly exclude complexherbal extracts (i.e., herbal extracts prepared from more than one, moretypically ore than five plants or plant parts) such as Tiger Balm, plantoils and essences.

[0032] Contemplated Uses

[0033] It is generally contemplated that compositions and formulationsaccording to the inventive subject matter are topically applied onto thesurface of a body of an animal, preferably a mammal, and most preferablya human. The term “surface of a body” as used herein refers to anysurface on a body of a person that is directly and manually accessibleby the same or other person, and particularly includes the scalp, neck,temples, and areas of skin superficial to a carotid artery, a temporalartery, and a vertebral artery. The term “superficial” as used hereinmeans in a proximity of no more than 1 cm, preferably no more than 7 mm,and more preferably no more than 4 mm. It is further contemplated thatsuch application will direct contemplated compounds to the cerebralcirculation. While it is generally contemplated that all methods oftopical application are considered suitable for use herein, particularlypreferred methods include manual application (e.g., rubbing in ormassaging in), application using a transdermal patch, and needle-lessinjection.

[0034] The term “cerebral circulation” as used herein refers to allblood vessels and compartments that supply blood and/or otherphysiological substances to and remove them from the cranial vault, andespecially encompass the arterial systems of the head and neck, thevenous system collecting and returning blood from the head to the trunk,the lymphatic systems draining the head and the cerebro-spinal fluidsystem bathing the brain, brain stem and spinal cord. Particularlycontemplated blood vessels supply blood and physiological substances tothe hypothalamus and are generally located above the trunk (i.e., areasincluding the neck and head).

[0035] In a preferred aspect of the inventive subject matter,approximately 200 mg to 1 g of contemplated compositions (e.g., 3.2% w/wtheophylline and 2% w/w ketoprofen in a transdermal formulation in creamform) is applied in equal portions to the temples of a person and gentlymassaged into the skin using circular rubbing motions to lessen aheadache. It is further preferred that the application is performed upononset of the headache.

[0036] However, it should be appreciated that numerous alternativeapplications are also suitable and include alternative amounts,alternative compositions, alternative areas on the patient's body, andalternative methods of application. For example, where contemplatedcompositions and formulations include relatively large amounts ofcontemplated compounds, applications of less than 500 mg are suitable(e.g., between 50 mg and 500 mg, and even less). Similarly, where theapplication area is relatively large, or where the composition orformulation includes relatively small amounts of contemplated compounds,application of more than 1 g (e.g. 1 g to 5 g, and even more) arecontemplated.

[0037] Similarly, the area of application need not be limited to an areasuperficial to a temporal artery (here: the temple), and numerousalternative areas are also considered suitable for application ofcontemplated compositions and formulations. For example, particularlypreferred alternative areas include a skin area superficial to a carotidartery and a skin area superficial to a vertebral artery as depicted inFIG. 1 (shaded areas). Alternatively, contemplated compositions orformulations may be applied to any area of the body, so long as theapplication will result in directing contemplated compounds to thecerebral circulation.

[0038] Where manual application is less desirable, numerous applicationsmethods other than manually rubbing are also contemplated and especiallyinclude application under occlusion (e.g., transdermal patch),electrophoretic application, needle-less injection, and sprayingcontemplated compositions and formulations onto the appropriate area. Itshould further be appreciated that the application may be performed bythe patient, or be partially or entirely performed by another person.

[0039] Depending on the purpose of application (e.g., application toreduce fever, application to improve cerebral circulation, applicationto improve the mood of a patient), the composition of contemplatedcompositions and formulations may vary significantly. For example, wherethe pharmacological agent is an anti-depressant, application may beperformed to improve the mood of the patient. On the other hand, wherethe pharmacological agent includes a fever reductant, application may beperformed to normalize the body temperature of the patient. Moreover,where the pharmacological agent includes an anti-coagulant orvaso-dilator, application may be performed to reduce deleterious effectsof impaired blood circulation (e.g., due to a stroke).

[0040] In another particularly preferred aspect of the inventive subjectmatter, contemplated compositions and formulations are employed to treata headache, wherein a tender spot associated with the headache isidentified on a body surface of a person. Contemplated compositions andformulations are then applied to the tender spot in an amount effectiveto lessen the headache. The term “tender spot” as used herein refers toa defined area on the body surface of a person that is (a) tender to thetouch and (b) perceptible as tender only when the person suffers from aheadache. Typically, a tender spot can be found by palpitation, andtender spots are often found on the parietal area (above the ears,forwards and behind), around the temples, or above the forehead. Tenderspots are less frequently found on the top and rear of the skull. Withrespect to applications other than treatment of a headache, amountsadministered to the patient, alternative compositions, areas on thepatient's body, and methods of application, the same considerations asdescribed above apply.

[0041] It should further be appreciated that contemplated compositionsand formulations may be used for prophylactic, temporary, permanent, andacute treatment of the condition that is to be treated by administrationof contemplated compositions and formulations.

[0042] Consequently, a method of directing a compound to a cerebralcirculation comprises a step in which a composition having apharmacologically active substance is provided, wherein the compositionis formulated in a transdermal formulation. In a further step, thetransdermal formulation is topically applied to an area of skinsuperficial to a carotid artery, a temporal artery, and/or a vertebralartery. Further contemplated methods include a method of treating aperson having a headache, in which a composition having apharmacologically active substance is provided. In a further step, atender spot associated with the headache on a body surface of the personis identified, and in a still further step, the composition is topicallyapplied to the tender spot in an amount effective to reduce theheadache.

[0043] In further contemplated aspects of the inventive subject matter,and especially where contemplated compositions and formulations areproduced and sold to the general public, it should be appreciated that amethod of marketing a product may include a step in which a skinpenetration enhancer is included as a component of the product. In afurther step, a person is instructed to identify a tender spotassociated with a headache on a body surface of the person, and in astill further step, the person is instructed to topically apply theproduct to the tender spot in an amount effective to reduce theheadache.

[0044] Alternatively, a method of marketing a product may include a stepin which a skin penetration enhancer and a pharmacological activesubstance are included as a component of the product. In a further step,the person is instructed to identify an area of skin superficial to atleast one of a carotid artery, a temporal artery, and a vertebralartery, and in yet another step, the person is instructed to apply theproduct topically to the area in an amount effective to direct thepharmacological active substance to a cerebral circulation.

[0045] With respect to the skin penetration enhancer, thepharmacologically active substance, application method, amount, andarea, the same considerations as described above apply. It is furtherpreferred that the instruction comprises providing a printedinformation, and especially contemplated printed information includeswritten instructions, a pictogram, a graph, and/or a photographic image.Alternatively, numerous known alternative instruction methods (e.g.,video class, internet class, person-to-person) are also consideredsuitable.

[0046] Cerebral Circulation and Directing a Compound to the CerebralCirculation

[0047] It is known that pain sensed in the head during a headacheoriginates in the optic division of the trigeminal nerve, whichenervates the cerebral vasculature. Swelling of the intra andextra-cranial vasculature were first identified by Wolff and colleaguesin the 1940's as key aspects of migraine [Wolff H. G.; Headaches andother head pain, 1st edition, Oxford University Press, London, 1948; andMeyer, Takashima, and Obara Headache Qtrly (1993) 4:222-235]. Thepressure sensed by swelling of these vessels is thought to betransmitted through the trigeminal ganglion to the thalamus, and then tothe cortex where the pain is experienced subjectively [Hargreaves inCephalalgia (2000) 20 Suppl 1:2-9].

[0048] There are numerous triggers of migraine. However, migrainesymptoms typically follow a uniform pattern, which are thought tooriginate in the hypothalmus upon integration of a variety of triggersby the cortex [Bruyn in Adv. Neurol. (1982) 33:151-169]. The concept ofbasilar arterial migraine, first presented by Bickerstaff[Lancet (1961)1:15-17] unifies the vascular perfusion deficiency with the multitude ofsymptoms by proposing that the lower cerebral circulation at the levelof the mid brain is the primary source of pathology. The thalamus andhypothalamus are the location of several regulatory nuclei of thesympathetic and parasympathetic regulatory centers, among them centralregulation of blood pressure, sleep, water balance and body temperature.

[0049] Based on these observations, the inventors contemplated that apharmacologically active agent for the treatment of headache must bedelivered through the cerebral circulation to the area of the brain stem(e.g., hypothalamus or post ganglionic visceromotor and viscerosensorysystem of the pericarotid plexus) in order to act effectively.Conventionally, this is accomplished by oral delivery, injection,inhalation, or absorption through the rectal mucosa in a quantitysufficient to achieve an effective concentration in the blood plasma.Indeed, the entire body (especially the plasma) of a patient must besaturated with the agent in a conventional approach to achieve atherapeutic effect (and concentration of the pharmacologically activeagent) in the brain. This process of saturating the plasma takesconsiderable time, except in the case of injection into a vein orinhalation, both of which are less preferable than oral administration.

[0050] The inventors have observed an unexpected result, in that topicalapplication of a pharmacologically active agent to the skin superficialto the arteries of the extracranial circulation will direct (i.e.,deliver) the agent to the cerebral circulation of the hypothalamus andmidbrain, and that such a delivery requires significantly less agent toachieve a therapeutically effective concentration. In particular, theinventors contemplate that a pharmacologically active agent applied tothe anterior triangle of the neck will penetrate the carotid sheath andenter the carotid blood supply of the brain and skull, or when appliedbelow the ear behind the jawbone, the agent can enter the externalcarotid artery and its branches, or when applied to the temples, theagent will enter the superficial temporal artery and lacrimal arteries,as well as the maxillary and deep temporal arteries (Branching from theexternal carotid between the temple and below the ear, the middlemeningeal and anterior tympanic arteries enter the posterior fossa, thechamber which contains the midbrain, through the jugular foramen and thecondylar canal).

[0051] The inventors' observations and contemplations are supported bythe fact that the circulation of the skull and scalp typically merge attheir ends into other arteries. With respect to the scalp, Gray'sAnatomy reads in pertinent parts “ . . . their anastomoses are so freethat as long as one is intact the detached scalp may be replaced withreasonable hope of its survival . . . ” (35th Brit. ed. p. 629). Thus,the zygomatico-orbital artery arises from the superficial temporalartery, runs across the zygomatic arch to anastmose with the lacrimaland palpebral branches of the opthalmic artery from inside the skull.The parietal branch of the superficial temporal artery curves upwardsand backwards on the side of the head and anastomoses with the oppositeartery, as well as the posterior auricular and occipital arteries. Theselatter arteries penetrate passages at the rear and base of the skull,where they supply the tympanic chamber, glands, and probably anastomosewith the meningeal artery. Therefore, the inventors contemplate that asubstance entering the arteries below the temples can be distributedwidely through the face and scalp, and through anastomoses enter thecerebral circulation of the skull.

[0052] Although the observations described herein and other experiments(data not shown) strongly suggest rapid delivery of effectiveconcentrations of pharmacologically active agents to the midbrain, theinventors do not wish to be limited to the theory as outlined above. Forexample, it is contemplated that in alternative delivery routes thepharmacologically active agent reaches the hypothalamus through thediploic channel, after having been distributed somewhat by the arterialcirculation. The venous drainage of the cerebral circulation passesthrough large sinuses before being gathered into the jugular vein andreturned to the heart. In the sluggish flow of these sinuses, which passdirectly behind and below the midbrain, the agent may diffuse out of thevenous blood and enter the midbrain directly. Alternatively, oradditionally, the agent may be entering the cerebrospinal fluid from thevenous or arterial flow and reach the areas of action in this manner.

EXAMPLES

[0053] The following examples illustrate exemplary compositions,formulations, and methods of use according to the inventive subjectmatter.

Example 1 (Exemplary Formulation with Aminophylline)

[0054] One kilogram of lecithin with suitable purity (>95% acetoneinsoluble) (e.g., Spectrum brand (LE 102)) is combined with 600 ml octylpalmitate in a blender (e.g., Waring 1 liter stainless steel) until themixture becomes a yellow, creamy fluid. Some lecithin granules may notbe dissolved. The mixture is subsequently transferred to 500 ml beakers(350 ml ±30 ml per beaker). A magnetic stirrer bar is added to eachbeaker and the mixtures are stirred for at least 12 hours. The resultingstirred solution has a dark amber color, and is translucent with asyrupy consistency.

[0055] The pharmacologically active substance (here: aminophylline) isdissolved in, or added to purified water, preferably in half theanticipated amount of purified water (here: in 50 ml) for the entirepreparation. The aqueous solution comprising the pharmacologicallyactive substance is slowly added to the lecithin syrup (e.g., byhand-stirring or small hand blender). The lecithin syrup will start togel as soon as the aqueous solution is added.

[0056] Following the addition of the active solution, continue to addwater one ml at a time (here:50 ml) while mixing. Thus, the exemplaryformulation (4% w/w with respect to pharmacologically active substance)comprises 1,000 gram lecithin, 510 gram octyl palmitate, 100 gram water,and 64.4 gram of aminophylline.

Example 2 (Exemplary Formulation with Penetration Enhancer)

[0057] The oil phase of this composition comprises 100 g (here: 10%,typically between 5-15%) granular lecithin of suitable purity (>95%acetone insoluble, with >92% phosphatidylcholine content) and 100 g(here: 10%, typically between 5-15%) isopropylmyristate. The water phasecomprises 200 g (here:20%) Polyoxamer F127 (Dow Corning) (Pluronic), 100mg sorbic acid, and 600 ml (here:60%) purified water. The activeingredient (here: e.g., 3.2% (w/w) theophylline) is dissolved in theappropriate phase (i.e., water soluble active ingredients in the waterphase, and lipid soluble active ingredients in the lipid phase). Thefinal formulation is then prepared by adding the water phase to the oilphase, and blending the two phases to completion. The pH was adjusted toless than 7.0, most typically to about 5.3-5.6 using acid or base.

Example 3 (Exemplary Formulation with Ketoprofen)

[0058] Same as in Example 2, comprising 3.2% (w/w) theophylline and 2%(w/w) Ketoprofen as active ingredients.

Example 4 (Exemplary Formulation with Penetration Enhancer andAcetaminophen)

[0059] Same as in Example 2, comprising 5% (w/w) acetaminophen as activeingredient.

Example 5 (Delivery of Acetaminophen to the Thalamic and HypothalamicRegion)

[0060] Acetaminophen is usually indicated for fever reduction and isthought to modulate the body temperature through interaction withthermoregulatory nuclei in the hypothalamus. Acetaminophen is typicallygiven as drops in children running a high fever at a dosage of about 160mg for a child of 2-3 years in age. Using oral delivery, acetaminophenwill enter the blood stream through the stomach, and will requireapproximately at least 20 minutes to achieve sufficient concentration inthe plasma to lower the fever.

[0061] To demonstrate delivery of pharmacologically active agents to thecerebral circulation (here: the thalamic and hypothalamic region), askin-penetrating formulation of acetaminophen as described in Example 4was applied in a single dosage of 25 mg acetaminophen (corresponding to500 mg of the formulation) to the temples of a group of patients with afever of between about 38.5° C. to about 39.5° C. In this group, thefever was reduced within three minutes in all of the twenty children andadults within the group. If transdermal delivery would have occurredsystemically, insufficient quantities of acetaminophen would have beenadministered for significant fever reduction since the total dosageapplied to the skin was less than 25 mg (and the amount penetrating theskin likely to be less than 15 mg). Moreover, significant feverreduction was achieved in about 10% of the time required for oraladministration. Therefore, and for reasons contemplated above, theinventors conclude that acetaminophen entered the cerebral circulationand reached the temperature-regulating center in the hypothalamus viathe temporal artery by topically applying a transdermal formulationcontaining acetaminophen. Of course, it should be recognized thatnumerous other fever reducing agents may also be employed incontemplated formulations. For example, it is contemplated that allknown non-steroid anti-inflammatory agents may be included (alone or incombination with other fever reducing agents), and a particularlypreferred non-steroid anti-inflammatory agent is acetaminophen oraspirin.

[0062] Consequently, the inventors contemplate that an essential aspectof directing a pharmacologically active agent to the cerebralcirculation includes formulation of the agent in a skinpenetration-enhancing vehicle (transdermal formulation). In formulationswithout penetration enhancers, only a fraction of a pharmacologicallyactive agent applied to the skin will penetrate percutaneously. Theamount that penetrates is typically limited by the amount applied, theway the material is spread out on the skin, and the speed with which thevehicle dries. Once the vehicle is dry, the agent will precipitate andno further material can enter the skin through the outer layer, thestratum corneum. Conventional vehicles can deliver no more thanmicrograms of agent through the stratum corneum under normalcircumstances [Flynn; “Topical and transdermal delivery—provinces ofrealism.” in Dermal and Transdermal Drug Delivery edition, CRC Press,Inc., Boca Raton, Fl, 1993, ISBN: 3804712231].

[0063] Alternative particularly suitable skin penetration enhancersinclude azone derivatives, synthetic and natural terpenes, oleic acid,N-methyl-2-pyrrolidone, epsilonaminocaproic acid esters, lecithinorganogels, pluronic-lecithin-organogels, aromaticS,S-dimethyliminosulfuranes, Padimate O, oil-water emulsions withsub-micron droplets, and capsaicin. Similarly, alternative xanthinederivatives include caffeine, theophylline, and aminophylline, inconcentrations preferably of at least 2% wt, more preferably at least 4%wt. Additionally, suitable formulations may further includemuscle-active substances, and particularly Ketoprofen (preferably in aconcentration of at least 0.5% wt to at least 10% wt). With respect tostill further alternative compounds, compositions, and formulations, thesame considerations as described above apply.

Example 6 (Treatment of Acute Headache)

[0064] The formulation of Example 1 was tested in a prospective clinicaltrial at the Pain Centers of America (415 North Crescent Drive BeverlyHills 90210, Calif). 155 patients were screened for headache history andother eligibility criteria, and 106 patients gave informed consent andentered the trial.

[0065] The temples were prepared by cleaning using witch hazel andalcohol astringent. One milliliter of the formulation was applied toeach temple and rubbed into the skin until it was absorbed completely.Headache relief was rapid, within 5 minutes of application for 81patients. Evaluation was determined by achieving a score of 7 out of 10on a VAS pain relief scale. Eleven of these patients had a return oftheir pain by 15 minutes. These patients reapplied the gel and eight outof the eleven had relief persisting at least one hour from the secondapplication. Consequently, the formulation was effective for 78 out of106 patients (74%). Interestingly, non-responders to the gel were heavyusers of analgesics, especially opioids. Consequently, it iscontemplated that success rates among the general population may well behigher than 74% of patients in this trial.

Example 6A (Treatment of Postdural Puncture Headache)

[0066] The formulation of Example 1 (with 10% aminophylline) was testedin a prospective clinical trial at the Pain Centers of America (415North Crescent Drive Beverly Hills 90210, Calif). 24 patients werescreened for headache history and other eligibility criteria, and 21patients gave informed consent and entered the trial.

[0067] The temples were prepared by cleaning using witch hazel andalcohol astringent. One milliliter of the formulation was applied toeach temple and rubbed into the skin until it was absorbed completely.Headache relief was rapid, within about 10 minutes of application for 18patients. Evaluation was determined by achieving a score of 7 out of 10on a VAS pain relief scale. Where pain symptoms reappeared (threepatients), the patients reapplied the gel and two of the three hadrelief persisting at least one hour from the second application.

Example 7 (Prophylactic Treatment of Headache)

[0068] For evaluation of prophylactic treatment of headache, formulationand application similar to the protocol as described in Example 6 wasused. Patients with a history of recurring headaches were sent home witha supply to test prophylactic efficacy and safety. The patients appliedthe gel to the temples before meals (3×daily). 62% did not experience asevere headache in the 30-day test period. The remaining subjects whohad a headache despite the use of the gel were asked to try anadditional dosage at bedtime during the second month of observation. Anadditional 11% found this an effective prophylaxis, yielding totalheadache prevention for 73% of patients. Furthermore, non-responders toprophylactic treatments still found immediate relief at the beginning ofthe headache using the medication. In the end, 86% of the respondingpatients in the study reported that the gel was the most effectiveabortive headache treatment they had ever used. It should further beappreciated that contemplated prophylactic treatments will also beeffective to prevent onset and/or lessen the severity of morningsickness and fibromyalgia, and especially preferred xanthine derivativesfor these symptoms include aminophylline).

Example 8 (Treatment of Acute Headache Using Tender Spot)

[0069] The formulation of Example 1 was tested in a prospective studyincluding 120 patients suffering from intermittent acute headaches. Afirst group of patients was instructed to locate a tender spot on theirscalp and to topically apply about 500 mg of the formulation to thetender spot, while a second group was instructed to apply about 500 mgof the formulation to the pulse points of their temples under a protocolsimilar as described in example 6. Application to the pulse points leadto rapid relief of the headache within 2-5 minutes in about 75% of thepatients, while application to the tender spot lead to almostinstantaneous relief in almost all of the patients.

[0070] While not wishing to be bound by a particular theory, it iscontemplated that the tender spot corresponds to the location wherearteries branching from the external carotid artery enter the skull andanastomose with arteries of the cerebral circulation. Swelling of thescalp arteries (as a result of the headache) constricts the vessels attheir passage through the skull bone, which is experienced as localpain, inflammation or tenderness.

[0071] Particularly contemplated alternative formulations include skinpenetration enhancers such as azone derivatives, synthetic terpenes,oleic acid, N-methyl-2-pyrrol-idone, epsilon-aminocaproic acid esters,pluronic-lecithin-organogels, or aromatic S,S-dimethyliminosulfurane.Especially contemplated pharmacologically active substances comprise avaso-active substance such as xanthine derivatives, and may furthercomprise a muscular-active substance (e.g., Ketoprofen). With respect tostill further alternative compounds, compositions, and formulations, thesame considerations as described above apply.

Example 9 (Treatment of Acute Headache Using Tender Spot and Ketoprofen)

[0072] The formulation of Example 3 (comprising 3.2% (w/w) theophyllineand 5% ketoprofen as active ingredients) was tested in a group of 25patients suffering from cervicogenic headache. The patients wereinstructed to rub approximately 1 ml of the formulation onto the back oftheir neck, and to reapply the formulation when needed. Where treatmentof headaches was performed using a protocol according to any one ofexamples 5-9, reduction in pain was observed in at least 60%, moretypically in at least 70%, and most typically in at least 85% of allpatient. The subjective pain relief was generally at least 4, moretypically at least 5, and most typically at least 7 on a 10-point scale(VAS pain relief scale).

Example 10 (Treatment of Transient or Non-transient Stroke)

[0073] Ischemic stroke is a temporary (e.g., transient) or permanentmedical condition characterized at least in part by the lack of oxygensupply to the brain, which may lead to reversible or irreversibleparalysis and/or cell death. Death or damage to a group of nerve cellsin the brain is often due to interrupted blood flow, caused by a bloodclot or blood vessel bursting. Depending on the area of the brain thatis damaged, a stroke can cause coma, paralysis, speech problems anddementia. Stroke may be treated by bolus injection of niacin, which isthought to dilate the arteries and permits blood flow to resume.

[0074] The inventor now discovered that stroke can be treated usingcompositions according to the inventive subject matter. Two patientswere treated for stroke, with the following results. Patient A wasbrought to the inventor by a relative. He demonstrated typical symptomsof aphasia, drooping of the right side of the face, and disorientation.A skin-penetrating formulation of niacin as described in Example 1 (seeabove, active ingredient 5% (w/w) niacin) was applied in a single dosageof 50 mg niacin (corresponding to 1 gram of formulation) to the anteriortriangle of the neck on the side exhibiting paralysis. The formulationwas gently massaged into the skin overlying the common carotid artery.The patient awoke from the disorientation within minutes, havingregained control of speech and without paralysis.

[0075] Patient B was treated at home, after his wife summoned theinventor. The patient was immobile in a bed, due to partial paralysisand was speaking nonsense syllables. He was in a state of distress, butunable to communicate. A skin-penetrating formulation of niacin asdescribed above was applied in a single dosage of 50 mg niacin(corresponding to 1 gram of formulation) to the anterior triangle of theneck on the side exhibiting paralysis. Within minutes the patientreturned to a normal state of consciousness and was able to communicate.In both of these patients there were no remaining symptoms of stroke,due to the speed of recovery.

[0076] Consequently, the inventors contemplate methods of treatment of apatient having an ischemic stroke, in which a composition including avasodilatory agent and/or an anticoagulant is provided. The compositionis included in a transdermal formulation, and the transdermalformulation is topically applied to at least one area of skinsuperficial to a carotid artery, a temporal artery, and a vertebralartery in an amount effective to deliver the vasodilatory agent and/oranticoagulant to the cerebral circulation, thereby improving blood flowin an area affected by reduction of blood flow.

[0077] With respect to suitable vasodilatory agents it is contemplatedthat all known vasodilators are considered appropriate. However,particularly preferred vasodilatory agents include niacin,nitroglycerin, various nitrates, and hydralazine. Still further itshould be appreciated that contemplated formulations may further includean anti-pyretic compound as previous studies have indicated beneficialeffects of hypothermal treatment in incomplete cerebral ischemia (seee.g., Hoffman et al. in J. Neurosurg. Anesthesiol. 1991;3:34-38).Alternatively, antipyretics may also be coadministered usingnon-transdermal routes. It is generally contemplated that all knownanti-pyretics are suitable for use herein, however, especiallycontemplated anti-pyretics include acetaminophen, dipyrone, and aspirin.

[0078] Thus, specific embodiments and applications of compositions andmethods for targeting cerebral circulation and treatment of headachehave been disclosed. It should be apparent, however, to those skilled inthe art that many more modifications besides those already described arepossible without departing from the inventive concepts herein. Theinventive subject matter, therefore, is not to be restricted except inthe spirit of the appended claims. Moreover, in interpreting both thespecification and the claims, all terms should be interpreted in thebroadest possible manner consistent with the context. In particular, theterms “comprises” and “comprising” should be interpreted as referring toelements, components, or steps in a non-exclusive manner, indicatingthat the referenced elements, components, or steps may be present, orutilized, or combined with other elements, components, or steps that arenot expressly referenced.

1. A method of directing a pharmacologically active substance to a cerebral circulation, comprising: providing a composition that includes a pharmacologically active substance; including the composition in a transdermal formulation; and topically applying the transdermal formulation to at least one area of skin superficial to a carotid artery, a temporal artery, and a vertebral artery, wherein the transdermal formulation is applied in an amount effective to deliver the pharmacologically active substance to the cerebral circulation.
 2. The method of claim 1 wherein the composition comprises a skin penetration enhancer selected from the group consisting of an azone derivative, a synthetic terpene, oleic acid, N-methyl-2-pyrrolidone, an epsilon-aminocaproic acid ester, a lecithin organogel, a pluronic-lecithin-organogel, and an aromatic S,S-dimethyl-iminosulfurane.
 3. The method of claim 1 wherein the composition comprises a skin penetration enhancer selected from the group consisting of natural terpenes, Padimate O, oil-water emulsions with sub-micron droplets, and capsaicin.
 4. The method of claim 1 wherein the pharmacologically active substance comprises a xanthine derivative.
 5. The method of claim 4 wherein the xanthine derivative comprises caffeine.
 6. The method of claim 4 wherein the xanthine derivative comprises theophylline.
 7. The method of claim 4 wherein the xanthine derivative comprises aminophylline.
 8. The method of claim 4 wherein the xanthine derivative has a concentration of at least 2% (wt).
 9. The method of claim 4 wherein the xanthine derivative has a concentration of at least 4% (wt).
 10. The method of claim 1 wherein the pharmacologically active substance comprises ketoprofen.
 11. The method of claim 10 wherein ketoprofen has a concentration of at least 0.5% (wt).
 12. The method of claim 10 wherein ketoprofen has a concentration of at least 4% (wt).
 13. The method of claim 1 wherein the step of topically applying is undertaken to lessen a headache.
 14. A method of treating a person having a headache, comprising: providing a composition that includes a pharmacologically active substance; identifying at least one tender spot associated with the headache on a body surface of the person; and topically applying the composition to the tender spot in an amount effective to reduce the headache.
 15. The method of claim 14 wherein the composition comprises a skin penetration enhancer.
 16. The method of claim 15 wherein the skin penetration enhancer is selected from the group consisting of an azone derivative, a synthetic terpene, oleic acid, N-methyl-2-pyrrolidone, an epsilon-aminocaproic acid ester, a pluronic-lecithin-organogel, and an aromatic S,S-dimethyliminosulfurane.
 17. The method of claim 14 wherein the composition comprises lecithin.
 18. The method of claim 14 wherein the pharmacologically active substance comprises a vaso-active substance.
 19. The method of claim 18 wherein the vaso-active substance comprises a xanthine derivative.
 20. The method of claim 18 wherein the pharmacologically active substance further comprises a muscular-active compound.
 21. The method of claim 20 wherein the muscular-active compound comprises ketoprofen.
 22. A composition comprising: at least one xanthine derivative and ketoprofen.
 23. The composition of claim 22 wherein the xanthine derivative comprises a substance selected from the group consisting of aminophylline, theophylline, and caffeine.
 24. The composition of claim 23 wherein the xanthine derivative and the ketoprofen are formulated in a lecithin-containing formulation.
 25. The composition of claim 23 wherein the xanthine derivative and the ketoprofen are formulated in a pluronic-lecithin-organogel formulation.
 26. A method of treating a person having a headache, comprising: providing a composition according to claim 22; identifying at least one tender spot associated with the headache on a body surface of the person having the headache; and topically applying the composition to the tender spot in an amount effective to reduce the headache.
 27. The method of claim 26 wherein the composition is in a skin penetration formulation.
 28. The method of claim 27 wherein the skin penetration formulation comprises a pluronic-lecithin-organogel formulation.
 29. The method of claim 26 wherein the xanthine derivative comprises a substance selected from the group consisting of aminophylline, theophylline, and caffeine.
 30. A method of marketing a product, comprising: including a skin penetration enhancer and a pharmacologically active substance as a component of the product; instructing a person to identify at least one tender spot associated with a headache on a body surface of the person; and instructing the person to topically apply the product to the tender spot in an amount effective to reduce the headache.
 31. The method of claim 30 wherein the product comprises a xanthine derivative and ketoprofen.
 32. The method of claim 30 wherein at least one of the steps of instructing comprises providing printed information.
 33. The method of claim 32 wherein the printed information comprises at least one of a pictogram, graph, and photographic image.
 34. A method of marketing a product, comprising: including a skin penetration enhancer and a pharmacological active substance as a component of the product; instructing a person to identify at least one area of skin superficial to at least one of a carotid artery, a temporal artery, and a vertebral artery; and instructing the person to topically apply the product to the area in an amount effective to direct the pharmacological active substance to a cerebral circulation of the person.
 35. The method of claim 34 wherein the skin penetration enhancer is selected from the group consisting of an azone derivative, a synthetic terpene, oleic acid, N-methyl-2-pyrrolidone, an epsilon-aminocaproic acid ester, a pluronic-lecithin-organogel, and an aromatic S,S-dimethyliminosulfurane.
 36. The method of claim 34 wherein the pharmacological active substance is selected from the group consisting of aminophylline, theophylline, and caffeine.
 37. The method of claim 34 wherein the product comprises a pluronic-lecithin-organogel and aminophylline.
 38. The method of claim 34 wherein the product further comprises ketoprofen.
 39. A method of prophylactic treatment of a patient to avoid a headache, comprising: providing a composition that includes a pharmacologically active substance; including the composition in a transdermal formulation; and topically applying the transdermal formulation to at least one area of skin superficial to a carotid artery, a temporal artery, and a vertebral artery, wherein the transdermal formulation is applied in an amount effective to prevent onset of the headache.
 40. A method of prophylactic treatment of a patient to avoid a headache, comprising: providing a composition that includes a pharmacologically active substance; identifying at least one tender spot associated with onset of the headache on a body surface of the person; and topically applying the composition to the tender spot in an amount effective to reduce the headache.
 41. A method of treatment of a patient having an ischemic stroke, comprising: providing a composition having at least one of a vasodilatory agent and an anticoagulant; including the composition in a transdermal formulation; topically applying the transdermal formulation to at least one area of skin superficial to a carotid artery, a temporal artery, and a vertebral artery; and wherein the transdermal formulation is applied in an amount effective to deliver the at least one of the vasodilatory agent and anticoagulant to a cerebral circulation of the patient, thereby improving blood flow in an area affected by reduction of blood flow.
 42. The method of claim 1 wherein the vasodilatory agent is selected from the group consisting of niacin, nitroglycerin, a nitrate, and hydralazine.
 43. The method of claim 43 wherein the vasodilatory agent is niacin and present in the transdermal formulation at a concentration of 5% (by weight).
 44. A method of reducing fever in a patient, comprising: providing a composition that includes a fever reducing agent; including the composition in a transdermal formulation; topically applying the transdermal formulation to at least one area of skin superficial to a carotid artery, a temporal artery, and a vertebral artery; and wherein the transdermal formulation is applied in an amount effective to deliver the fever reducing agent to a cerebral circulation, thereby reducing an elevated body temperature of the patient.
 45. The method of claim 44 wherein the fever reducing agent is a non-steroid anti-inflammatory agent.
 46. The method of claim 45 wherein the non-steroid anti-inflammatory agent is acetaminophen, dipyrone, or aspirin. 